1. Field of the Invention
The present invention features methods for detecting at least one specified neurological disorder in a subject. In one aspect, the invention relates to novel polynucleotides for detecting the neurological disorder. In a related aspect, the invention provides methods for identifying, analyzing, and using the polynucleotides. Further provided are screening methods for detecting therapeutic compounds with capacity to treat the neurological disorder. The present invention has a variety of uses including detecting a specified motor neuron disorder in a patient.
2. Background
Neurological disorders can significantly impact the central nervous system (CNS) and motor neuron units. For example, certain neurological disorders of the CNS are known to adversely affect the brain and associated structures. Neurological disorders affecting motor neuron units have been grouped into motor neuron diseases and peripheral neuropathies. See generally Kandel, E. R. et al; (1991) in Principles of Neuroscience, Appleton & Lange, Norwalk, Conn.; and Rowland, L. P. (ed.) (1982) in Human Motor Neuron Diseases. New York. Raven Press.
An illustrative motor neuron disease is amyotrophic lateral sclerosis (ALS). ALS has been reported to be a chronic neuromuscular disorder having recognized clinical manifestations. For example, it has been suggested that degeneration of cortical and spinal/bulbar motor neurons may play a key role in the disorder. ALS is nearly always fatal. About 95% of all ALS cases are sporadic, with many of the remaining cases showing autosomal dominant inheritance. See e.g., Kuncl R. W. et al., (1992) Motor Neuron Diseases In Diseases of the Nervous System, Asbury et al. eds. (Philadelphia W. B. Saunders) pp. 1179–1208; Brown, R. H., (1996) Amer. Neurol. 30:145; Siddique, T. and Deng., H. X. (1996) Hum. Mol. Genetics 5:1465).
Specific CNS disorders have been also described. In particular, some have been attributed to cholinergic, dopaminergic, adrenergic, serotonergic deficiencies or combinations thereof. CNS disorders of severe impact include pre-senile dementia (sometimes referred to as Alzheimer's disease (AD) or early-onset Alzheimer's disease), senile dementia (dementia of the Alzheimer's type), Parkinson's disease (PD), and Huntington's disease (HD, sometimes referenced as Huntington's chorea). Such CNS disorders are well-represented in the human population. See generally; Gusella, J. F. et al. (1983) Nature 306: 234; Borlauer. W. and Jprmuloewoca. P. (eds.) (1976); Adv. in Parkinsonism: Biochemistry, Physiology, Treatment. Fifth International Symposium on Parkinson's Disease (Vienna) Basel: Roche; and references cited therein.
Significant attention has been directed towards understanding the etiology of motor neuron diseases. For example, abnormal levels of certain excitotoxic neurotransmitters have been reported to adversely contribute to many motor neuron diseases. In particular, glutamate-mediated excitotoxicity is recognized to have a critical role in ALS. See e.g., Rothstein J. D. et al., (1990) Ann. Neurol. 28: 18.; Rothstein J. D. et al. (1992) N. Engl. Med. 326: 1464; Rothstein J. D. et al. (1993) PNAS (USA) 90: 6591; and Lacomblez, L. et al., (1996) Lancet 347: 1179.
There has been substantial efforts towards understanding mechanisms for reducing glutamate levels in the nervous system. For example, high-affinity, sodium-dependent glutamate transport is one reported means of inactivating glutamate. In particular, astrocytic excitatory amino acid transporter 2 (EAAT 2) proteins are believed to have substantial functions in that inactivation. See e.g., Rothstein J. D. et al. (1994) Neuron 28: 18; Rothstein J. D. et al., (1995) Ann. Neurol. 38: 78, and references cited therein.
In particular, investigations have suggested that EAAT 2 is a predominant glutamate transporter. More particularly, certain antisense knockdown studies have been reported to demonstrate that EAAT 2 loss can lead to excitotoxic neuronal degeneration and progressive motor impairment. Studies of ALS and other neurodegenerative disorders have related impaired glutamate transport to loss of the EAAT 2 protein. In particular, up to 60% to 70% of the sporadic ALS patients examined have a 30% to 95% loss of the EAAT 2 protein. See e.g., Haugeto et al., supra; Rothstein J. D., et al., (1996) Neuron 16: 675; Bristol, L. A. and Rothstein, J. D. (1996) Ann. Neurol. 39: 676.
There have been attempts to treat or prevent neurological disorders of the CNS and the motor neuron units. However, most existing therapies do not always stem the development or severity of the disorders in afflicted patients. See e.g., Rowell, (1987) Adv. Behav. Biol. 31: 191; Rinne, et al. Brain Res. (1991) 54: 167; U.S. Pat. No. 5,210,076 to Berliner; Yurek, D. M. (1990) Ann. Rev. Neurosci. 13: 415, and Rowland et al. supra.
Substantial research effort has focussed on developing effective methods for detecting neurological disorders in patients. However, many existing methods are not always effective or reliable. For example, some methods are optimized to analyze post-mortem samples. Such methods provide little benefit for the afflicted patient. Other methods rely on testing living patients for specific cognitive or motor skills. However, such tests can be difficult to perform or interpret in some settings.
Accordingly, there is a need in the field for effective and reliable methods for detecting neurological disorders in a living patient. There is general recognition that such methods would positively impact many existing therapies. It would be particularly desirable to have methods for detecting specific neurological disorders in a living patient before disease onset or at an early stage of disease progression.